Insulin Resistance, Non-Alcoholic Fatty Liver Disease and Type 2 Diabetes Mellitus: Clinical and Experimental Perspective.

It has been generally accepted that insulin resistance (IR) and reduced insulin secretory capacity are the basic pathogenesis of type 2 diabetes mellitus (T2DM). In addition to genetic factors, the persistence of systemic inflammation caused by obesity and the associated threat of lipotoxicity increase the risk of T2DM. In particular, the main cause of IR is obesity and subjects with T2DM have a higher body mass index (BMI) than normal subjects according to recent studies. The prevalence of T2DM with IR has increased with increasing BMI during the past three decades. According to recent studies, homeostatic model assessment of IR was increased compared to that of the 1990s. Rising prevalence of obesity in Korea have contributed to the development of IR, non-alcoholic fatty liver disease and T2DM and cutting this vicious cycle is important. My colleagues and I have investigated this pathogenic mechanism on this theme through clinical and experimental studies over 20 years and herein, I would like to summarize some of our studies with deep gratitude for receiving the prestigious 2023 Sulwon Award.

Nitrogen-Doped Activated Hollow Carbon Nanofibers with Controlled Hierarchical Pore Structures for High-Performance, Binder-Free, Flexible Supercapacitor Electrodes.

Carbon nanofibers (CNFs) are a fascinating electrode material for energy storage devices due to their one-dimensionality, interconnected networks, and chemical stability. However, a relatively low specific surface area of CNFs hinders their use as supercapacitor electrodes. Here, nitrogen-doped hollow CNFs with hierarchical pore structures are prepared via electrospinning of core-shell polymer nanofibers and subsequent carbonization and activation under an ammonia atmosphere. Hierarchical pore structures with micro-, meso-, and macropores are controlled by an ammonia etching effect during the carbonization of polymer nanofibers. In addition, a hollow structure in CNFs is obtained by thermal decomposition of the core polymer during the carbonization/activation. The nitrogen-doped activated hollow CNFs (ahCNFs) exhibited an exceptionally high specific surface area of 3618 m2/g with increased mesopores. Thus, a symmetric supercapacitor using ahCNFs electrodes with a 6 M KOH aqueous electrolyte provides a high specific capacitance of 208 F/g at a current density of 1 A/g, a high energy density of 7.22 W h/kg at a power density of 502 W/kg, a good rate capability, and cyclic stability. Moreover, the freestanding ahCNFs are used for flexible supercapacitor electrodes without any binder. This work demonstrates the great potential of highly porous ahCNFs for high-performance energy storage devices.

Efficacy and Safety of IDegAsp in a Real-World Korean Population with Type 2 Diabetes Mellitus.

Background: This study investigated the real-world efficacy and safety of insulin degludec/insulin aspart (IDegAsp) in Korean adults with type 2 diabetes mellitus (T2DM), whose insulin treatment was switched to IDegAsp. Methods: This was a multicenter, retrospective, observational study comprising two 26-week treatment periods, before and after switching to IDegAsp, respectively. Korean adults with uncontrolled T2DM treated with basal or premix insulin (±oral antidiabetic drugs) were enrolled. The primary objective was to compare the degree of glycosylated hemoglobin (HbA1c) change in each 26-week observation period. The analyses included changes in HbA1c, fasting plasma glucose (FPG), body weight, proportion of participants achieving HbA1c <7.0%, hypoglycemic events, and total daily insulin dose (ClinicalTrials.gov, number NCT04656106). Results: In total, 196 adults (mean age, 65.95 years; mean T2DM duration, 18.99 years) were analyzed. The change in both HbA1c and FPG were significantly different between the pre-switching and the post-switching period (0.28% vs. -0.51%, P<0.001; 5.21 mg/dL vs. -23.10 mg/dL, P=0.005), respectively. After switching, the rate of achieving HbA1c <7.0% was significantly improved (5.10% at baseline vs. 11.22% with IDegAsp, P=0.012). No significant differences (before vs. after switching) were observed in body weight change, and total daily insulin dose. The rates of overall and severe hypoglycemia were similar in the two periods. Conclusion: In real-world clinical practice in Korea, the change of insulin regimen to IDegAsp was associated with an improvement in glycemic control without increase of hypoglycemia, supporting the use of IDegAsp for patients with T2DM uncontrolled with basal or premix insulin.

Risk of Cardiovascular Disease according to Baseline Low-Density Lipoprotein Cholesterol Level in Different Age Groups in Korean Diabetes Population: A Cohort Study.

BACKGRUOUND: The association between low-density lipoprotein (LDL-C) levels and cardiovascular disease (CVD) risk in different age groups within the diabetes mellitus (DM) population remains unclear. The cohort study was conducted to investigate this relationship. METHODS: We assessed the 2009 to 2012 Korean National Health Screening and National Health Insurance Service records, with follow-up to the primary outcome (myocardial infarction [MI] or stroke) or December 2018. After excluding the participants with a history of MI or stroke, 2,227,394 participants with DM were included and categorized according to baseline LDL-C levels and age. Cox proportional hazards modeling was conducted. The CVD risk of age <40 years and LDL-C <70 mg/dL was set as the reference. In each age group, LDL-C <70 mg/dL was used as a reference for the subgroup analysis. RESULTS: The cut-off LDL-C value for increased MI risk in each age group varied (<40 years old, LDL-C ≥160 mg/dL: hazard ratios [HR], 2.03; 95% confidence interval [CI], 1.644 to 2.506) (40-49-year-old, LDL-C <115 mg/dL: HR, 1.245; 95% CI, 1.04 to 1.489) (50-59-year-old, LDL-C <115 mg/dL: HR, 1.21; 95% CI, 1.014 to 1.445) (60-69-year-old, LDL-C <145 mg/dL: HR, 1.229; 95% CI, 1.022 to 1.479) (≥70 years old group, LDL-C <100 mg/dL: HR, 1.238; 95% CI, 1.018 to 1.504). The cut-off LDL-C values for increased stroke risk varied in each age subgroup (<40 years old, LDL-C ≥160 mg/dL: HR, 1.395; 95% CI, 1.094 to 1.779) (40-49-year-old, LDL-C <145 mg/dL: HR, 1.13; 95% CI, 1.019 to 1.253) (50-59-year-old, LDL-C <160 mg/dL: HR, 1.079; 95% CI, 1.008 to 1.154) (60-69-year-old, LDL-C <130 mg/dL: HR, 1.07; 95% CI, 1.022 to 1.119) (≥70 years old, LDL-C <115 mg/dL: HR, 1.064; 95% CI, 1.019 to 1.112). CONCLUSION: The effect of LDL-C on the risk of CVD differs depending on the age of the population with DM.

Inhibition of Sodium-Glucose Cotransporter-2 during Serum Deprivation Increases Hepatic Gluconeogenesis via the AMPK/AKT/FOXO Signaling Pathway.

BACKGRUOUND: Sodium-dependent glucose cotransporter 2 (SGLT2) mediates glucose reabsorption in the renal proximal tubules, and SGLT2 inhibitors are used as therapeutic agents for treating type 2 diabetes mellitus. This study aimed to elucidate the effects and mechanisms of SGLT2 inhibition on hepatic glucose metabolism in both serum deprivation and serum supplementation states. METHODS: Huh7 cells were treated with the SGLT2 inhibitors empagliflozin and dapagliflozin to examine the effect of SGLT2 on hepatic glucose uptake. To examine the modulation of glucose metabolism by SGLT2 inhibition under serum deprivation and serum supplementation conditions, HepG2 cells were transfected with SGLT2 small interfering RNA (siRNA), cultured in serum-free Dulbecco's modified Eagle's medium for 16 hours, and then cultured in media supplemented with or without 10% fetal bovine serum for 8 hours. RESULTS: SGLT2 inhibitors dose-dependently decreased hepatic glucose uptake. Serum deprivation increased the expression levels of the gluconeogenesis genes peroxisome proliferator-activated receptor gamma co-activator 1 alpha (PGC-1α), glucose 6-phosphatase (G6pase), and phosphoenolpyruvate carboxykinase (PEPCK), and their expression levels during serum deprivation were further increased in cells transfected with SGLT2 siRNA. SGLT2 inhibition by siRNA during serum deprivation induces nuclear localization of the transcription factor forkhead box class O 1 (FOXO1), decreases nuclear phosphorylated-AKT (p-AKT), and p-FOXO1 protein expression, and increases phosphorylated-adenosine monophosphate-activated protein kinase (p-AMPK) protein expression. However, treatment with the AMPK inhibitor, compound C, reversed the reduction in the protein expression levels of nuclear p- AKT and p-FOXO1 and decreased the protein expression levels of p-AMPK and PEPCK in cells transfected with SGLT2 siRNA during serum deprivation. CONCLUSION: These data show that SGLT2 mediates glucose uptake in hepatocytes and that SGLT2 inhibition during serum deprivation increases gluconeogenesis via the AMPK/AKT/FOXO1 signaling pathway.

Glucagon-Like Peptide Receptor Agonist Inhibits Angiotensin II-Induced Proliferation and Migration in Vascular Smooth Muscle Cells and Ameliorates Phosphate-Induced Vascular Smooth Muscle Cells Calcification.

BACKGRUOUND: Glucagon-like peptide-1 receptor agonist (GLP-1RA), which is a therapeutic agent for the treatment of type 2 diabetes mellitus, has a beneficial effect on the cardiovascular system. METHODS: To examine the protective effects of GLP-1RAs on proliferation and migration of vascular smooth muscle cells (VSMCs), A-10 cells exposed to angiotensin II (Ang II) were treated with either exendin-4, liraglutide, or dulaglutide. To examine the effects of GLP-1RAs on vascular calcification, cells exposed to high concentration of inorganic phosphate (Pi) were treated with exendin-4, liraglutide, or dulaglutide. RESULTS: Ang II increased proliferation and migration of VSMCs, gene expression levels of Ang II receptors AT1 and AT2, proliferation marker of proliferation Ki-67 (Mki-67), proliferating cell nuclear antigen (Pcna), and cyclin D1 (Ccnd1), and the protein expression levels of phospho-extracellular signal-regulated kinase (p-Erk), phospho-c-JUN N-terminal kinase (p-JNK), and phospho-phosphatidylinositol 3-kinase (p-Pi3k). Exendin-4, liraglutide, and dulaglutide significantly decreased the proliferation and migration of VSMCs, the gene expression levels of Pcna, and the protein expression levels of p-Erk and p-JNK in the Ang II-treated VSMCs. Erk inhibitor PD98059 and JNK inhibitor SP600125 decreased the protein expression levels of Pcna and Ccnd1 and proliferation of VSMCs. Inhibition of GLP-1R by siRNA reversed the reduction of the protein expression levels of p-Erk and p-JNK by exendin-4, liraglutide, and dulaglutide in the Ang II-treated VSMCs. Moreover, GLP-1 (9-36) amide also decreased the proliferation and migration of the Ang II-treated VSMCs. In addition, these GLP-1RAs decreased calcium deposition by inhibiting activating transcription factor 4 (Atf4) in Pi-treated VSMCs. CONCLUSION: These data show that GLP-1RAs ameliorate aberrant proliferation and migration in VSMCs through both GLP-1Rdependent and independent pathways and inhibit Pi-induced vascular calcification.

Docosahexanoic Acid Attenuates Palmitate-Induced Apoptosis by Autophagy Upregulation via GPR120/mTOR Axis in Insulin-Secreting Cells.

Background: Polyunsaturated fatty acids (PUFAs) reportedly have protective effects on pancreatic ß-cells; however, the underlying mechanisms are unknown. Methods: To investigate the cellular mechanism of PUFA-induced cell protection, mouse insulinoma 6 (MIN6) cells were cultured with palmitic acid (PA) and/or docosahexaenoic acid (DHA), and alterations in cellular signaling and apoptosis were examined. Results: DHA treatment remarkably repressed caspase-3 cleavage and terminal deoxynucleotidyl transferase-mediated UTP nick end labeling (TUNEL)-positive red dot signals in PA-treated MIN6 cells, with upregulation of autophagy, an increase in microtubule- associated protein 1-light chain 3 (LC3)-II, autophagy-related 5 (Atg5), and decreased p62. Upstream factors involved in autophagy regulation (Beclin-1, unc51 like autophagy activating kinase 1 [ULK1], phosphorylated mammalian target of rapamycin [mTOR], and protein kinase B) were also altered by DHA treatment. DHA specifically induced phosphorylation on S2448 in mTOR; however, phosphorylation on S2481 decreased. The role of G protein-coupled receptor 120 (GPR120) in the effect of DHA was demonstrated using a GPR120 agonist and antagonist. Additional treatment with AH7614, a GPR120 antagonist, significantly attenuated DHA-induced autophagy and protection. Taken together, DHA-induced autophagy activation with protection against PA-induced apoptosis mediated by the GPR120/mTOR axis. Conclusion: These findings indicate that DHA has therapeutic effects on PA-induced pancreatic ß-cells, and that the cellular mechanism of ß-cell protection by DHA may be a new research target with potential pharmacotherapeutic implications in ß-cell protection.

Impact of Antidiabetic Drugs on Clinical Outcomes of COVID-19: A Nationwide Population-Based Study.

Background: Inconsistent results have been reported regarding the association between the use of antidiabetic drugs and the clinical outcomes of coronavirus disease 2019 (COVID-19). This study aimed to investigate the effect of antidiabetic drugs on COVID-19 outcomes in patients with diabetes using data from the National Health Insurance Service (NHIS) in South Korea. Methods: We analyzed the NHIS data of patients aged ≥20 years who tested positive for COVID-19 and were taking antidiabetic drugs between December 2019 and June 2020. Multiple logistic regression analysis was performed to analyze the clinical outcomes of COVID-19 based on the use of antidiabetic drugs. Results: A total of 556 patients taking antidiabetic drugs tested positive for COVID-19, including 271 male (48.7%), most of whom were in their sixties. Of all patients, 433 (77.9%) were hospitalized, 119 (21.4%) received oxygen treatment, 87 (15.6%) were admitted to the intensive care unit, 31 (5.6%) required mechanical ventilation, and 61 (11.0%) died. Metformin was significantly associated with the lower risks of mechanical ventilation (odds ratio [OR], 0.281; 95% confidence interval [CI], 0.109 to 0.720; P=0.008), and death (OR, 0.395; 95% CI, 0.182 to 0.854; P=0.018). Dipeptidylpeptidase-4 inhibitor (DPP-4i) were significantly associated with the lower risks of oxygen treatment (OR, 0.565; 95% CI, 0.356 to 0.895; P=0.015) and death (OR, 0.454; 95% CI, 0.217 to 0.949; P=0.036). Sulfonylurea was significantly associated with the higher risk of mechanical ventilation (OR, 2.579; 95% CI, 1.004 to 6.626; P=0.049). Conclusion: In patients with diabetes and COVID-19, metformin exhibited reduced risks of mechanical ventilation and death, DPP- 4i was linked with lower risks of oxygen treatment and death, while sulfonylurea was related to the increased risk of mechanical ventilation.

Association between underweight and risk of heart failure in diabetes patients.

BACKGROUND: The risk of heart failure (HF) in underweight diabetes mellitus (DM) patients has rarely been studied. We conducted a cohort study to investigate the association between underweight (BMI < 18.5 kg/m2) and BMI change over time and the risk of HF in patients with type 2 DM. METHODS: We utilized the health screening data from the National Health Insurance Service and the Korean National Health Screening database from 2009 to 2012, with follow-up until December 2018. Participants with DM were categorized into four groups based on their BMI at 4 years before study inclusion and BMI at the study entry: (1) Always Normal Weight (BMI at 4 years ago/BMI at study entry ≥18.5/≥18.5 kg/m2, reference group); (2) Transitioned to Underweight (≥18.5/<18.5 kg/m2); (3) Transitioned to Normal Weight (<18.5/≥18.5 kg/m2) and (4) Always Underweight (<18.5/<18.5 kg/m2). Participants were followed until the development of HF or at the end of the follow-up. Initial screening data included participants with DM who had the health screening during the study period (n = 2,746,079). Participants aged <20 years (n = 390), those who did not undergo health examination 4 years prior (n = 1,306,520), and those with missing data (n = 77,410) were excluded. Participants diagnosed with HF before study participation (n = 81,645) and within 1 year of study enrolment (n = 11,731) were excluded. After applying exclusion criteria, 1,268,383 participants were finally included in the analysis. The primary outcome was the development of HF. We employed Cox proportional hazards models, adjusting for various confounding factors, to assess the risk of developing HF. RESULTS: Median follow-up duration was 6.88 years and men were 63.16%. The mean ages of each groups were as follows: Always Normal Weight (57.92 ± 11.64 years), Transitioned to Underweight (62 ± 13.5 years), Transitioned to Normal Weight (56.6 ± 15.29 years) and Always Underweight (57.76 ± 15.35 years). In comparison with the Always Normal Weight group (n = 1,245,381, HF = 76,360), Transitioned to Underweight group (≥18.5/<18.5 kg/m2, n = 9304, HF = 880, adjusted Hazard Ratio (aHR)1.389, 95% confidence interval (CI) 1.3-1.485) or Transitioned to Normal Weight (<18.5/≥18.5 kg/m2, n = 6024, HF = 478, aHR 1.385, 95% CI 1.266-1.515) exhibited an increased risk of HF. The highest risk was observed in the Always Underweight group (<18.5/<18.5 kg/m2, n = 7674, HF = 665, aHR 1.612, 95% CI 1.493-1.740). CONCLUSIONS: Underweight was significantly associated with the risk of HF in the DM population. Active surveillance for HF in an underweight DM population is needed.

Diuron-induced fetal Leydig cell dysfunction in in vitro organ cultured fetal testes.

Diuron is a phenylurea herbicide widely used in the agricultural industry. In recent years, the risk of infertility and developmental defects has increased due to exposure to environmental pollutants. In this study, we investigated the toxicity of diuron in fetal mouse testes using three-dimensional organ cultures. Fetal testes derived from embryonic day (E) 14.5 were cultured with 200 µM diuron for 5 days. The results revealed that diuron did not impair fetal germ cell proliferation or the expression levels of germ cell markers such as Ddx4, Dazl, Oct 4, Nanog, Plzf, and TRA 98. Similarly, the gene or protein expression of the Sertoli cell markers Sox9 and Wt1 in diuron-exposed fetal testes did not change after 5 days of culture. In contrast, diuron increased fetal Leydig cell markers (FLC), Cyp11a1, Cyp17a1, Thbs2, and Pdgf α, and decreased adult Leydig cell (ALC) markers, Sult1e1, Hsd173, Ptgds, and Vcam1. However, 3-ßHSD, an FLC and ALC marker, was consistently maintained upon exposure to diuron in fetal testes compared to non-treated groups. In conclusion, our study demonstrates that diuron negatively impacts Fetal Leydig cell development, although it does not affect germ and Sertoli cells.

Nonalcoholic Fatty Liver Disease and the Risk of Thyroid Cancer Among Young Adults in South Korea.

CONTEXT: Nonalcoholic fatty liver disease (NAFLD) is a hepatic manifestation of metabolic syndrome. Obesity and metabolic syndrome are known risk factors for thyroid cancer. OBJECTIVE: We investigated the association between NAFLD and thyroid cancer risk in young adults. METHODS: This nationwide cohort study included 1 135 967 participants aged 20 to 39 years who underwent 4 consecutive health screenings in South Korea. NAFLD was categorized using the fatty liver index (FLI), as follows: ≥60, 30 to 60, and <30. The cumulative FLI points were defined as the number of times participants had a FLI of ≥30 (0-4). RESULTS: During a median follow-up of 5.2 years, 4126 participants (0.36%) were newly diagnosed with thyroid cancer. Compared with the participants with an FLI of <30, those with an FLI of 30 to 60 (men: hazard ratio [HR] 1.36 [95% CI, 1.22-1.51] and women: HR 1.44 [1.21-1.70]) and those with an FLI of ≥60 (men: HR 1.71 [1.53-1.92] and women: HR 1.81 [1.46-2.25]) had a significantly higher risk of thyroid cancer. Participants with higher cumulative FLI points had a higher risk of thyroid cancer compared to those with a cumulative FLI point of 0 (P < .001). During the follow-up period, the participants with an increased FLI exhibited an increased risk of thyroid cancer. CONCLUSION: NAFLD was associated with an increased risk of thyroid cancer in young adults. Repeatedly elevated FLI and progression of NAFLD were associated with an increased risk of thyroid cancer in this study.

Differential Impact of Obesity on the Risk of Diabetes Development in Two Age Groups: Analysis from the National Health Screening Program.

BACKGRUOUND: The effect of obesity on the development of type 2 diabetes mellitus (DM) in different age groups remains unclear. We assessed the impact of obesity on the development of DM for two age groups (40-year-old, middle age; 66-year-old, older adults) in the Korean population. METHODS: We analyzed Korean National Health Insurance Service data of 4,145,321 Korean adults with 40- and 66-year-old age without DM, between 2009 and 2014. Participants were followed up until 2017 or until the diagnosis of DM. We assessed the risk of DM based on the body mass index and waist circumference of the participants. Multiple confounding factors were adjusted. RESULTS: The median follow-up duration was 5.6 years. The association of general and abdominal obesity with the risk of DM development was stronger in the 40-year-old group (general obesity: hazard ratio [HR], 3.566, 95% confidence interval [CI], 3.512 to 3.622; abdominal obesity: HR, 3.231; 95% CI, 3.184 to 3.278) than in the 66-year-old group (general obesity: HR, 1.739; 95% CI, 1.719 to 1.759; abdominal obesity: HR, 1.799; 95% CI, 1.778 to 1.820). In the 66-year-old group, abdominal obesity had a stronger association with the development of DM as compared to general obesity. In the 40-year-old group, general obesity had a stronger association with the risk of DM development than abdominal obesity. CONCLUSION: The influence of general and abdominal obesity on the development of DM differed according to age. In older adults, abdominal obesity had a stronger association with DM development than general obesity.

Direct methane protonic ceramic fuel cells with self-assembled Ni-Rh bimetallic catalyst.

Direct methane protonic ceramic fuel cells are promising electrochemical devices that address the technical and economic challenges of conventional ceramic fuel cells. However, Ni, a catalyst of protonic ceramic fuel cells exhibits sluggish reaction kinetics for CH4 conversion and a low tolerance against carbon-coking, limiting its wider applications. Herein, we introduce a self-assembled Ni-Rh bimetallic catalyst that exhibits a significantly high CH4 conversion and carbon-coking tolerance. It enables direct methane protonic ceramic fuel cells to operate with a high maximum power density of ~0.50 W·cm-2 at 500 °C, surpassing all other previously reported values from direct methane protonic ceramic fuel cells and even solid oxide fuel cells. Moreover, it allows stable operation with a degradation rate of 0.02%·h-1 at 500 °C over 500 h, which is ~20-fold lower than that of conventional protonic ceramic fuel cells (0.4%·h-1). High-resolution in-situ surface characterization techniques reveal that high-water interaction on the Ni-Rh surface facilitates the carbon cleaning process, enabling sustainable long-term operation.

Exposures to humidifier disinfectant and various health conditions in Korean based on personal exposure assessment data of claimants for compensation.

BACKGROUND: Humidifier disinfectants (HDs) were commonly used household chemicals to prevent microbial growth in a humidifier water tank in South Korea. A growing body of evidence has indicated that its airborne exposure can induce severe lung injury. However, there has been low awareness of other health outcomes in HD users. This study aimed to evaluate health conditions appealed by claimants for compensation in relation with an increased exposure to HD. METHODS: From survey data of personal HD exposure assessment of claimants for compensation in Korea, we included a total of 4,179 subjects [cases in each dataset were defined by nine reported health conditions, i.e., pneumonia, asthma, cardiovascular disease, respiratory disease, otorhinolaryngologic disease, brain disease (including cerebrovascular disease), dermatological disease, lung cancer, and all cancers]. HD exposures was considered as the following exposure criteria: exposure duration, exposure proximity, exposure direction, chemical type, cumulative exposure time, indoor air concentration, and cumulative exposure level. Logistic regression models were used to evaluate the associations between HD exposure and health conditions. RESULTS: After adjusting for sociodemographic and health behavioral factors and other chemical exposures (households, environmental, and occupational exposures), an increase in cumulative HD exposure time was significantly associated with risks of all nine diseases (all p-trends < 0.05). An increase in HD exposure duration was associated with asthma, respiratory disease, otorhinolaryngologic disease, dermatological disease, all cancers, and lung cancer (p-trends < 0.05). Indoor HD concentration was associated with only pneumonia (p-trend = 0.015). CONCLUSIONS: Our findings suggest that cumulative exposures to airborne HD might potentially increase the risk of various reported health outcomes.

Novel edible films fabricated with HG-type pectin extracted from different types of hybrid citrus peels: Effects of pectin composition on film properties.

This study investigated the valorization of novel HG-type hybrid citrus pectins derived from three cultivars: Setoka (ST), Kanpei (KP), and Shiranui (SH), and their application as packaging materials. The physicochemical properties of these pectins and their corresponding films were evaluated and compared to commercial citrus pectin. Significant variations were observed in pectin yield (18.15-24.12 %) and other physicochemical characteristics, such as degree of esterification (DE), degree of methoxylation (DM), and monosaccharide composition, among the different cultivars. All hybrid citrus pectins were classified as high-methoxy pectin types (66.67-72.89 %) with typical structural configurations like commercial citrus pectin. However, hybrid citrus pectin films exhibited superior physical properties, including higher mechanical strength, flexibility, and lower water solubility than commercial citrus pectin film, while maintaining similar transparency and moisture content. Additionally, the films displayed smooth and uniform surface morphology, confirming their excellent film-forming properties. Correlation analysis revealed that DE positively influenced mechanical properties (r = 1.0). Furthermore, the monosaccharide composition of pectins showed strong relationships (r = 0.8-1.0) with the film's mechanical and barrier properties. These findings highlight the potential of hybrid citrus pectin as potential packaging material, and the knowledge of the structure-function relationship obtained in this study could be useful for the tailored modification of citrus pectin-based packages.

Coronary Artery Calcium Score as a Sensitive Indicator of Cardiovascular Disease in Patients with Type 2 Diabetes Mellitus: A Long-Term Cohort Study.

BACKGRUOUND: Coronary artery calcium score (CACS) has become an important tool for evaluating cardiovascular disease (CVD). This study evaluated the significance of CACS for future CVD through more than 10 years of follow-up in asymptomatic Korean populations with type 2 diabetes mellitus (T2DM) known to have a relatively low CACS burden. METHODS: We enrolled 981 asymptomatic T2DM patients without CVD at baseline who underwent CACS evaluation using multidetector computed tomography between January 2008 and December 2014. They were grouped into five predefined CACS categories based on Agatston scores and followed up by August 2020. The primary endpoint was incident CVD events, including coronary, cerebrovascular, and peripheral arterial disease. RESULTS: The relative risk of CVD was significantly higher in patients with CACS ≥10, and the significance persisted after adjustment for known confounders. A higher CACS category indicated a higher incidence of future CVD: hazard ratio (95% confidence interval) 4.09 (1.79 to 9.36), 12.00 (5.61 to 25.69), and 38.79 (16.43 to 91.59) for 10≤ CACS <100, 100≤ CACS <400, and CACS ≥400, respectively. During the 12-year follow-up period, the difference in event-free survival more than doubled as the category increased. Patients with CACS below 10 had very low CVD incidence throughout the follow-up. The receiver operating characteristic analysis showed better area under curve when the CACS cutoff was 10 than 100. CONCLUSION: CACS can be a sensitive marker of CVD risk. Specifically, CACS above 10 is an indicator of CVD high-risk requiring more intensive medical treatment in Koreans with T2DM.

T-2 mycotoxin Induces male germ cell apoptosis by ROS-mediated JNK/p38 MAPK pathway.

T-2 mycotoxin, a type A trichothecene toxin that, specifically, causes male and female reproductive toxicity. We evaluated T-2 toxin toxicity in testes from neonatal testes after in vitro tissue cultured. Additionally, current study focuses on the molecular mechanism of toxicity and germ cell damage in GC-1 spermatogonial cells. Mouse testicular fragments were subjected to T-2 toxin (0-20 nM) during days 5 of in vitro culture. Testicular germ cell number were reduced and downregulated the expression of corresponding markers depending on the exposure concentration of T-2 toxin; however, Sertoli cell markers and steroidogenic enzyme expression increased when treated with 20 nM T-2 toxin. The cell viability decreased, apoptosis increased, and pro-apoptotic protein expression increased in 5-20 nM T-2 toxin-exposed spermatogonia. Moreover, T-2 toxin generated reactive oxygen species (ROS) and induced mitochondrial dysfunction, indicating that activation of p38 MAPK signaling triggered by ROS is involved in the apoptotic molecular mechanism of T-2 toxin. T-2 toxin induced the phosphorylation of ERK1/2, c-Jun, JNK/SAPK, p38, and p53, and the subsequent inhibition of AKT phosphorylation. The upregulation of genes related to apoptosis and MAPK/JNK signaling was consistently observed in cells exposed to T-2 toxin. These results indicate that T-2 toxin triggers apoptotic cell death in germ cells through the triggering of ROS-mediated JNK/p38-MAPK signaling pathways.

Efficacy of Gemigliptin Add-on to Dapagliflozin and Metformin in Type 2 Diabetes Patients: A Randomized, Double-Blind, Placebo-Controlled Study (SOLUTION).

BACKGRUOUND: This study evaluated the efficacy and safety of add-on gemigliptin in patients with type 2 diabetes mellitus (T2DM) who had inadequate glycemic control with metformin and dapagliflozin. METHODS: In this randomized, placebo-controlled, parallel-group, double-blind, phase III study, 315 patients were randomized to receive either gemigliptin 50 mg (n=159) or placebo (n=156) with metformin and dapagliflozin for 24 weeks. After the 24-week treatment, patients who received the placebo were switched to gemigliptin, and all patients were treated with gemigliptin for an additional 28 weeks. RESULTS: The baseline characteristics were similar between the two groups, except for body mass index. At week 24, the least squares mean difference (standard error) in hemoglobin A1c (HbA1c) changes was -0.66% (0.07) with a 95% confidence interval of -0.80% to -0.52%, demonstrating superior HbA1c reduction in the gemigliptin group. After week 24, the HbA1c level significantly decreased in the placebo group as gemigliptin was administered, whereas the efficacy of HbA1c reduction was maintained up to week 52 in the gemigliptin group. The safety profiles were similar: the incidence rates of treatment-emergent adverse events up to week 24 were 27.67% and 29.22% in the gemigliptin and placebo groups, respectively. The safety profiles after week 24 were similar to those up to week 24 in both groups, and no new safety findings, including hypoglycemia, were noted. CONCLUSION: Add-on gemigliptin was well tolerated, providing comparable safety profiles and superior efficacy in glycemic control over placebo for long-term use in patients with T2DM who had poor glycemic control with metformin and dapagliflozin.

Association of physical activity with total and cause-specific mortality in patients with diabetes: A nationwide population-based cohort study.

AIMS: Physical inactivity is a modifiable risk factor for cardiovascular disease (CVD) in patients with type 2 diabetes mellitus (T2DM); however, little is known about its association with mortality due to other causes. Herein, we investigated the association between physical activity (PA) and cause-specific mortality in patients with T2DM. METHODS: We analyzed data from the Korean National Health Insurance Service and claims database of adults with T2DM aged >20 years at baseline (n = 2,651,214). Each participant's PA volume was measured as the metabolic equivalent of tasks (METs)-min per week, and hazard ratios of all-cause and cause-specific mortality relative to PA levels were estimated. RESULTS: During the 7.8 years of follow-up, all-cause, CVD, respiratory, cancer, and other causes of mortality were lowest in patients engaged in vigorous PA. MET-min/week was inversely associated with mortality after adjusting for covariates. The reduction in total and cause-specific mortality was greater in patients aged ≥65 years than in those aged <65 years. CONCLUSIONS: Increasing PA may facilitate a reduction in mortality from various causes, especially among older patients with T2DM. Clinicians should encourage such patients to increase their daily PA levels to reduce their risk of mortality.

Reprint of: Outcomes of Arthroscopic All-Inside Repair Are Improved Compared to Transtibial Pull-Out Repair of Medial Meniscus Posterior Root Tears.

PURPOSE: The purpose of the present study was to compare the clinical outcomes of patients who underwent an all-inside repair (with a bony trough) versus transtibial pull-out repair in medial meniscus posterior root tears (MMPRTs). METHODS: We retrospectively investigated consecutive patients who underwent MMPRT repairs in nonacute tears in age over 40 from November 2015 to June 2019. All patients were divided into a transtibial pull-out repair group and an all-inside repair group. Different surgical techniques were used during different time frames. All patients were followed-up for a minimum of 2 years. The data collected included the International Knee Documentation Committee (IKDC) Subjective, Lysholm, and Tegner activity scores. Magnetic resonance imaging (MRI) was performed at the 1-year follow-up to assess meniscus extrusion, signal intensity, and healing. RESULTS: The final cohort consisted of 28 patients in the all-inside repair group and 16 in the transtibial pull-out repair group. In the all-inside repair group, the IKDC Subjective, Lysholm, and Tegner scores improved significantly at the 2-year follow-up. In the transtibial pull-out repair group, the IKDC Subjective, Lysholm, and Tegner scores did not improve significantly at the 2-year follow-up. Postoperative extrusion ratio increased in both groups, and patient-reported outcomes at follow-up did not differ between the two groups The change in the extrusion ratio was significantly less in the all-inside repair group (P = .009), as was the postoperative meniscus signal (P = .011). Postoperative MRI revealed significantly better healing in the all-inside group (P = .041). CONCLUSION: All-inside repair improved the functional outcome scores. Radiologically, all-inside repair was better than transtibial pull-out repair. All-inside repair may be a viable MMPRT treatment option. LEVEL OF EVIDENCE: III, retrospective cohort study.